1. ¹Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine, Rochester, NY, USA
2. ²Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA

Correspondence: Dr RS Freeman, Department of Pharmacology and Physiology, University of Rochester School of Medicine, 601 Elmwood Avenue, Room 4-6718, Rochester, NY 14642, USA. E-mail: robert_freeman@urmc.rochester.edu

³Current address: Department of Anatomy and Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.

Received 2 September 2008; Revised 20 January 2009; Accepted 12 February 2009; Published online 23 March 2009.

Abstract

von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the proapoptotic Bcl-2 family protein BIM_EL and are more resistant to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL). Reintroducing pVHL into VHL-null cells increased the half-life of BIM_EL protein without affecting its mRNA expression, and overexpressing pVHL inhibited BIM_EL polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIM_EL protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIM_EL expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIM_EL protein stability in RCC cells, and that destabilization of BIM_EL in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.